News / 10 January 2017
First appeared at the Monash University Biomedicine Discovery Institute, 20 December 2016.
Throughout 2016 Associate Professor Max Cryle and his collaborators, from the Max Planck Institute for Medical Research, have used published molecular structures of antibiotic resistant golden staph (Staphylococcus aureus), to see how we might overcome the resistance with new super-antibiotics.
Associate Professor Cryle tells us that in most situations golden staph is harmless; it lives on the skin and in the nose.
“If, however, it enters the body it can cause a range of mild to severe infections – it can even cause death,” he said.
Structural work done on golden staph at The Alfred shows that in antibiotic resistant staph the cell walls of the bacteria are thicker, and so, regular antibiotics fail to penetrate this wall to reach where they need to, to be lethal. Associate Professor Cryle and his team want to work out how to recreate and optimise antibiotics in the lab so they pack a bigger punch when faced with resistant staph.
Something you might not know about antibiotics is that they are almost exclusively naturally occurring; they are grown by fermentation in thousand litre tanks and researchers then extract the antibiotics. However, to synthesise such antibiotics in a lab is rather difficult. Associate Professor Cryle and his team are looking at novel ways to synthesise (that is, grow) their own antibiotics. This way, they can engineer them to behave in specific ways, with the aim to have stronger, more efficient antibiotics to break through thick cell walls.
Because the team know, chemically, the end game — what the peptide antibiotic needs to ‘look’ like to be effective — their job is to work out how to manipulate connections between particular molecules so that they have the shape and the function they need.
An easy feat, this is not. But Associate Professor Cryle said that he and his group have made tremendous progress over the year. And, they only have one step to go.
“We all know that shape and function are intrinsically linked,” Associate Professor Cryle said.
“By having control over the shape we can control the function. There are quite a few different steps involved in doing this though. And, depending on the order of the steps, we get differing results.”
“To link or fold the peptides we add enzymes, but how we add them, which ones will work and when we add them makes quite a difference. We’ve had success when we add two enzymes first and then add the third one. This gets us three quarters of the way to the final shape we want. And, to be clear, this shape is provided by the extra rings, and the rings are made by adding enzymes.”
By adding enzymes we force the peptides to join in particular orientations. Currently it isn’t possible to control all aspects of the natural compounds we use for fighting bacteria and infections. The key part of molecule, in terms of the function and the part that does the killing and binding, are very difficult to manipulate and change. They are also impossible to make on a commercially viable basis.
“Modifying what is on the outside can make a big difference to the function of the antibiotics, but if we can make them fold in the right ways then we have more control over the core of the antibiotics,” Associate Professor Cryle said.
“When we have successfully made all four rings, meaning we have folded the molecule into the shape we want, we can test our antibiotics. We do this by letting the staph bacteria grow and then adding in our new antibiotic and watching how it is either killed or the growth of it is inhibited.”
Associate Professor Cryle said his team will continue working on the final step.
“We are close, but not quite there yet. Watch this space though, I think 2017 might be the magic year."
Associate Professor Cryle is a researcher at the Monash Biomedicine Discovery Institute. He is also an Associate Investigator at the Australian Research Council's Centre of Excellence in Advanced Molecular Imaging, and a European Molecular Biology Laboratory group leader.
About the Australian Research Council's Centre of Excellence in Advanced Molecular Imaging
The $39 million ARC-funded Imaging CoE develops and uses innovative imaging technologies to visualise the molecular interactions that underpin the immune system. Featuring an internationally renowned team of lead scientists across five major Australian Universities and academic and commercial partners globally, the Centre uses a truly multi scale and programmatic approach to imaging to deliver maximum impact.
The Imaging CoE is headquartered at Monash University with four collaborating organisations – La Trobe University, the University of Melbourne, University of New South Wales and the University of Queensland.